WO2017045612A1 - Dérivé de pyrimidine inhibiteur de la pim kinase, son procédé de préparation et son application dans la préparation de médicaments - Google Patents

Dérivé de pyrimidine inhibiteur de la pim kinase, son procédé de préparation et son application dans la préparation de médicaments Download PDF

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WO2017045612A1
WO2017045612A1 PCT/CN2016/099040 CN2016099040W WO2017045612A1 WO 2017045612 A1 WO2017045612 A1 WO 2017045612A1 CN 2016099040 W CN2016099040 W CN 2016099040W WO 2017045612 A1 WO2017045612 A1 WO 2017045612A1
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difluorophenyl
pyrimidin
group
fluoro
pyridinecarboxamide
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PCT/CN2016/099040
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Chinese (zh)
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葛羽
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上海吉铠医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to medicinal chemistry, and in particular to PIM kinase inhibitors, methods for their preparation and their use in pharmacy.
  • PIM kinases are three homologous serine/threonine kinases belonging to the family of calmodulin-dependent protein kinases (CAMK). Studies have shown that PIM kinase is widely expressed in hematopoietic tissues (J. Biol. Chem., 280, 14168-14176, 2005; Blood, 105, 4477-4483, 2005) and plays an important role in cell survival and proliferation. And overexpressed in human cancer tumors as well as in inflammatory conditions (J. Exp. Med., 201, 259-266, 2005; Biochem. Soc. Trans., 32, 315-319, 2004). Therefore, PIM kinase is increasingly being used to study targets for the treatment of tumors and immunomodulatory drugs.
  • CAMK calmodulin-dependent protein kinases
  • PIM-1 Provirus Integration of Maloney 1 gene is a site for frequent insertion of provirus in Moloney murine leukemia virus-induced T cell lymphoma, and PIM-1 kinase is also named (Cell, 37, 141-150, 1984). It was later found that the gene encoding PIM-2 (Provirus Integration of Maloney 2) also had the same weakness (J. Clin. Invest., 115, 2679-2688, 2005). PIM-3 was originally named KID-1 (Kinase Induced by Depolarization 1) and was later renamed for its highly consistent protein sequence with PIM-1 (71% amino acid repeat) (Nature, 428, 332-337, 2005; Cell, 56, 673- 682, 1989).
  • PIM-1, 2, 3 are overexpressed in many hematological tumors (PNAS USA, 86, 8857-8861, 1989).
  • PIM-1 has been found to be more expressed during the development of prostate cancer (J. Clin. Pathol., 59, 285-288, 2006)
  • PIM-2 is found in human chronic lymphocytic leukemia and non-Hodgkin's lymphoma. Expression is increased (Leuk. Lymph., 45, 951-955, 2004), while abnormal expression of PIM-3 is considered for hepatic fibroma (Int. J. Cancer, 114, 209-218, 2005) and pancreatic cancer (Cancer Res)
  • PIM-1, 2, 3 usually respond to stimulation by growth factors and cytokines, thus contributing to the survival and spread of hematopoietic cells. Mice that knocked out the PIM-1, 2, and 3 genes survived normally, but were smaller and spread during hematopoietic cell proliferation. The response to growth factors has also been reduced. If only one of the three PIMs was removed, there was no significant effect on the mice, and the functions of the three PIMs were overlapped (Cell, 56, 673-682, 1989). Substrates of action of PIM kinase include Bcl-2 family members that regulate apoptosis (FEBS Letters, 571, 43-49, 2004), p21 that regulates cell cycle (Biochim. Biophys.
  • PIM kinase inhibitors can significantly inhibit the proliferation of tumor cells including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and chronic tumor growth.
  • CML Granulocyte leukemia
  • NHL non-Hodgkin's lymphoma
  • MM multiple myeloma
  • PIM kinase inhibitors also have a good effect on solid tumors overexpressing PIM kinase, including pancreatic cancer (Cancer Biol. Ther. 7 (9), 1352-9, 2008 Cancer Res. 2006; 66 (13 ): 6741-7; Cancer Res. 70 (24), 10288–10298, 2010), Prostate Cancer (Prostate, 65(3), 276-86, 2005; Prostate, 73(13), 1462–1469, 2013) , Liver cancer (J. Surg. Res., 153 (1), 17-22, 2009; Int. J. Cancer, 114 (2), 209-18, 2005), gastric cancer (J. Cancer Res. Clin. Oncol. , 134 (4), 481-8, 2008) and bladder cancer (J. Exp. Clin. Cancer Res., 29, 161, 2010).
  • pancreatic cancer Cancer Biol. Ther. 7 (9), 1352-9, 2008 Cancer Res. 2006; 66 (13 ): 6741-7; Cancer Res. 70 (24), 10288–
  • PIM kinase expression is accompanied by activation of T-cells
  • PIM-1/3 inhibitors are effective in treating enteritis caused by CD4+ T-cells.
  • the oral clinical trial drug AR452530 can at least reduce rectal inflammation, glandular loss, edema and mucosal hyperplasia by 80% (Cellular Immunology, 272, 200–213, 2012). Therefore, PIM inhibitors can also be used to treat T-cell mediated diseases such as inflammatory bowel disease.
  • Both formula A and formula B are PIM inhibitors.
  • R a , R b and R c are the same, the only difference is the 5-position substituent on pyridine ring 1
  • general formula A is a hydrogen atom
  • general formula B is a fluorine atom.
  • the literature data shows that in all 29 pairs of compounds, whether the 5-position substituent is H or F has little effect on the PIM activity of these compounds and does not alter the ability of the compound to inhibit PIM-1 enzyme activity.
  • R 6 is a cyclic structure.
  • R 3 is changed from H to other substituents, the steric hindrance increases, which hinders the free rotation of the R 6 ring, thereby increasing their activity.
  • R 3 is replaced by F or CF 3 , the highest activity is improved by nearly 6 times, an average of 4.19 times, by increasing the lipophilicity of the molecule, thereby further enhancing the ability of the compound to inhibit PIM-1 activity. See Table 2 of Example 57 for specific data.
  • the technical problem to be solved by the present invention is to study a novel compound of a PIM kinase inhibitor, and to design and prepare a medicament for treating T-cell mediated inflammation such as cancer, multi-directional drug resistance and inflammatory bowel disease.
  • the present invention provides a PIM kinase inhibitor having the formula:
  • the compound of the formula I according to the invention is a PIM kinase inhibitor of the structure of a pyrimidine compound.
  • the invention also provides stereoisomers, tautomers and pharmaceutically acceptable salts of the compounds of formula I.
  • R 1 is -H, -NHR 4 , halogen (F, Cl, Br, I), -OH, -OC 1-3 hydrocarbyl, -SH, -SC 1-3 hydrocarbyl, C 1-3 hydrocarbyl, halo Base, haloethyl, -CN and -NO 2 ;
  • R 2 is -H, -NHR 4 , halogen (F, Cl, Br, I), -OH, -SH, -OC 1-3 hydrocarbon group with or without a substituent, -SC 1-3 hydrocarbon group, C 1-3 hydrocarbyl and C 3-7 cycloalkyl, halomethyl, haloethyl, -CN and -NO 2 ;
  • R 3 is -NHR 5 , halogen (F, Cl, Br, I), -OH, -SH, -OC 1-3 hydrocarbon group with or without a substituent, -SC 1-3 hydrocarbon group, C 1- 3 hydrocarbyl and C 3-7 cycloalkyl, halomethyl, haloethyl, -CN and -NO 2 ;
  • R 5 is a C 1-8 hydrocarbon group, a C 1-8 alkoxy group, a C 3-7 cycloalkyl group with or without a substituent;
  • R 6 is a C 3-7 cycloalkyl group, a 4-7 membered heterocyclic group, a 5-10 membered aryl group and a heterocyclic aryl group with or without a substituent; the cyclic hydrocarbon group, an aryl group and a heterocyclic group
  • the substituents on the group may be halogen (F, Cl, Br, I), -CN, -NH 2 , -NHR 7 , C 1-4 hydrocarbyl, C 1-4 halohydrocarbyl, C 3-7 cycloalkyl.
  • R 7 is -H or with or without a substituted C 1-4 hydrocarbyl group
  • R 22 is a C 1-8 hydrocarbon group with or without a substituent or a group defined by the formula:
  • R 15 , R 16 , R 17 , R 18 , R 19 are each -H or a C 1-8 hydrocarbon group with or without a substituent
  • G 1 is CH 2 or N
  • G 2 is NR 28 , CHR 29 or O;
  • B1 and B2 are 0, 1, 2 or 3;
  • B3 is 0, 1, 2;
  • R 26 and R 27 are each -H or a C 1-8 hydrocarbon group with or without a substituent
  • R 30 is -H or a C 1-8 hydrocarbon group with or without a substituent
  • the substituent in the present invention may be selected from a hydroxyl group, a nitro group, an amino group, an imino group, a cyano group, a halogen group, a thio group, a sulfonyl group, a thioamido group, a thiol group, or a thiol group, unless otherwise specified.
  • R 1 is -H, -NHR 4 , halogen (F, Cl, Br, I ), -OH, -SH, -OC 1-3 hydrocarbyl group with or without a substituent, -SC 1-3 hydrocarbyl group, C 1-3 hydrocarbyl group and C 3-7 cycloalkyl group, -CN and -NO 2
  • R 1 is -H, -NH 2 , halogen (F, Cl, Br, I), -OH, -CN and -NO 2 ; further preferably R 1 is -H, -NH 2 , -F.
  • R 2 is -H, -NHR 4 , halogen (F, Cl, Br, I), -OH, -SH, -OC 1-3 hydrocarbyl group with or without a substituent, -SC 1-3 hydrocarbyl group, C 1-3 hydrocarbyl group and C 3-7 cycloalkyl group, -CN and -NO 2 ;
  • R 2 is -H, halogen (F, Cl, Br, I), -CN; further preferably R 2 is -H, halogen (F, Cl, Br, I).
  • R 3 is -NHR 5 , halogen (F, Cl, Br, I), -OH, -SH, -OC 1-3 hydrocarbyl group with or without a substituent, -SC 1-3 hydrocarbyl group, C 1-3 hydrocarbyl group and C 3-7 cycloalkyl group, halomethyl group, halogenated B a group, -CN and -NO 2 ; preferably R 3 is halogen (F, Cl, Br, I), a C 1-3 hydrocarbon group with or without a substituent, and a -OC 1-3 hydrocarbon group, a halogenated methyl group , -CN and -NO 2 ; further preferably R 3 is halogen (F, Cl, Br, I), -CF 3 , and -CN; still more preferably R 3 is halogen (F, Cl, Br, I) and -NHR 5 , halogen (F, Cl, Br, I), -OH, -SH, -OC 1-3 hydrocarby
  • R 22 is a cyclobutane group with or without a substituent.
  • R 22 is a cyclohexane group, a pyrrolidinyl group, a piperidinyl group or an azacycloheptyl group; and the substituent group may have 1 to 4 substituents, which may be selected separately From halogen (F, Cl, Br, I), -NH 2 , -OH, methylamino, ethylamino, propylamino, dimethylamino, dieth
  • the compound of Formula I, and stereoisomers, tautomers thereof, and pharmaceutically acceptable salts thereof wherein R22 is cyclobutanemethyl with or without a substituent , cyclopentylmethyl, cyclohexanemethyl, cycloheptylmethyl, azetidinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, azepanylmethyl , butylene alkylmethyl, tetrahydrofuranylmethyl, tetrahydropyranylmethyl; further preferably R 22 is cyclohexanemethyl, pyrrolidinylmethyl, piperidinylmethyl, azepan An alkylmethyl group; may have from 1 to 4 substituents on the substituent group, and may be independently selected from the group consisting of halogen (F, Cl, Br, I), -NH 2 , -OH, methylamino group ,ethylamino, propylamin
  • R22 is cyclo
  • the compound of Formula I, and the stereoisomers, tautomers and pharmaceutically acceptable salts thereof, wherein R22 is a C2-5 hydrocarbon group with or without a substituent may have up to 4 substituents, which may be halogen (F, Cl, Br, I), NH 2 , methylamino, ethylamine, propylamino, dimethylamino, diethylamino, respectively.
  • the compounds of formula I and their stereoisomers, tautomers and pharmaceutically acceptable salts thereof, are shown in Table 2.
  • alkyl refers to an alkyl group that does not contain a hetero atom.
  • the term includes straight-chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, undecyl, dodecyl, and the like.
  • the term also includes branched chain isomers of straight chain alkyl groups, including but not limited to, the following groups: -CH (CH 3) 2, CH (CH 3) (CH 2 CH 3), CH (CH 2 CH 3 ) 2 , -C(CH 3 ) 3 , -C(CH 2 CH 3 ) 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 2 CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , -CH 2 C(CH 2 CH 3 ) 3 , -CH(CH 3 )CH(CH 3 )(CH 2 CH 3 ), - CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH 2 CH(CH 3
  • alkyl includes primary alkyl, secondary alkyl and tertiary alkyl.
  • Preferred alkyl groups include straight chain and branched alkyl groups having from 1 to 12 carbon atoms.
  • a preferred "alkyl group” relates to the definition of straight chain C l-4 alkyl such as methyl, ethyl, n-propyl and n-butyl.
  • Preferred alkyl groups include C 3-5 define further branched chain alkyl group, including -CH (CH 3) 2, -CH 2 CH (CH 3) 2, -CH (CH 3) CH 2 CH 3, -C (CH 3 ) 3 , -CH(CH 3 )CH 2 CH 2 CH 3 , -CH(CH 3 )CH(CH 3 ) 2 , -CH 2 CH(CH 3 )CH 2 CH 3 , -CH 2 CH 2 CH ( CH 3 ) 2 and -CH(CH 2 CH 3 ) 2 and the like.
  • alkenyl refers to an alkyl group as defined above wherein at least one point of unsaturation, i.e., wherein two adjacent carbon atoms are joined by a double bond.
  • alkynyl as used herein relates to an alkyl group wherein two adjacent carbon atoms are joined by a triple bond.
  • alkoxy refers to -OR, wherein R is alkyl.
  • hydrocarbyl as used herein is a generic term for alkyl, alkenyl and alkynyl groups.
  • halogen refers to a fluorine, chlorine, bromine and iodine (F, Cl, Br, I) group.
  • Haloalkyl means an alkyl group substituted by one or more halogen atoms.
  • haloalkyl includes monohaloalkyl, dihaloalkyl, trihaloalkyl and the like.
  • Typical monohaloalkyl groups include -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH(F)CH 3 , -CH(Cl)CH 3 ;
  • typical dihaloalkanes groups include -CHC1 2, -CHF 2, -CC1 2 CH 3, -CH (Cl) CH 2 Cl, -CH 2 CHC1 2, -CH 2 CHF 2;
  • trihaloalkyl typically comprises -CC1 3, -CF 3 , -CC1 2 CH 2 Cl, -CF 2 CH 2 F, -CH(Cl)CHC1 2 , -CH(F)CHF 2 ;
  • typical perhaloalkyl groups include -CC1 3 , -CF 3 , -CC1 2 CC1 3 , -CF 2 CF 3 .
  • amino refers to the group NH 2.
  • alkylamino refers to a group -NRR' wherein R and R' are each independently selected from hydrogen or lower alkyl, wherein R and R' are not H at the same time.
  • arylamino refers to a group -NRR' wherein R is aryl and R' is hydrogen, lower alkyl or aryl.
  • aralkylamino refers to a group -NRR' wherein R is lower aralkyl and R' is hydrogen, lower alkyl, aryl or lower aralkyl.
  • cyano refers to the group -CN.
  • nitro refers to the group -NO 2 .
  • alkoxyalkyl refers to a group -alk1-0-alk2 wherein alk1 is alkyl or alkenyl and alk2 is alkyl or alkenyl.
  • lower alkoxyalkyl refers to an alkoxyalkyl group wherein alk1 is lower alkyl or lower alkenyl and alk2 is lower alkyl or lower alkenyl.
  • aryloxyalkyl refers to the group monoalkyl-0-aryl.
  • aralkyloxyalkyl refers to a group of alkylene-0-aralkyl wherein the aralkyl group is a lower aralkyl group.
  • arylaminocarbonyl refers herein to a group -C(O)-NRR' wherein R is aryl and R' is hydrogen, lower alkyl or aryl.
  • Aralkylaminocarbonyl refers herein to a group -C(O)-NRR' wherein R is lower aralkyl and R' is hydrogen, lower alkyl, aryl or lower aralkyl.
  • aminosulfonyl refers to the group -S(O) 2 NH 2 "substituted aminosulfonyl” as used herein to refer to a group wherein R is lower alkyl and R' is hydrogen or lower alkyl. -S(O) 2 NRR'.
  • aralkylaminosulfonylaryl refers herein to the group aryl-S(O) 2- NH aralkyl wherein the aralkyl group is a lower aralkyl group.
  • carbonyl refers to the divalent group -C(O)-.
  • cycloalkyl refers to a mono or polycyclic carbocyclic alkyl substituent.
  • Carbocycloalkyl is a cycloalkyl group in which all ring atoms are carbon.
  • Typical cycloalkyl substituents have from 3 to 8 backbone (ie, ring) atoms wherein each backbone atom is a carbon or heteroatom.
  • heterocycloalkyl refers to a cycloalkyl substituent having from 1 to 5, and more typically from 1 to 4, heteroatoms in the ring structure. Suitable heteroatoms for use in the compounds of the invention are nitrogen, oxygen and sulfur.
  • heterocycloalkyl moieties include, for example, morpholino, piperazinyl, piperidinyl and the like.
  • Carbocycloalkyl is a cycloalkyl group in which all ring atoms are carbon.
  • polycyclic as used herein, when used in connection with a cycloalkyl substituent, refers to both fused and non-fused alkyl cyclic structures.
  • partially unsaturated cycloalkyl means that there is at least one point of unsaturation, ie wherein two adjacent ring atoms pass through a double bond or three A cycloalkyl group bonded to a bond.
  • Illustrative examples include cyclohexynyl, cyclopentynyl, cyclopropenyl, cyclobutane, and the like.
  • substituted heterocyclic ring refers to any 3 or 4 membered ring containing one hetero atom selected from nitrogen, oxygen and sulfur or containing one to three selected from one to three.
  • a 5- or 6-membered ring of a hetero atom of nitrogen, oxygen or sulfur wherein the 5-membered ring has 0-2 double bonds and the 6-membered ring has 0-3 double bonds; wherein the nitrogen and sulfur atoms are Optionally oxidized; and includes any bicyclic group wherein any of the above heterocyclic rings are fused to a phenyl ring or other 5- or 6-membered heterocyclic ring as defined above independently.
  • heterocycloalkyl refers to a 5- or 6-membered ring containing one to three heteroatoms selected from nitrogen, oxygen or sulfur, wherein the ring has no double bonds.
  • heterocyclic- C5 alkyl refers to a 6-membered ring containing 5 carbon atoms and one hetero atom such as N.
  • heterocycle includes rings wherein the nitrogen is a heteroatom and a partially saturated and fully saturated ring.
  • Preferred heterocycles include, for example, dinitrogen (diazapiny1), pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, piperidinyl, pyridazinyl, piperazinyl, pyrazinyl, N- Methyl piperazinyl, azetidinyl, N-methylazetidinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl , morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, fluorenyl, quinolyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzox
  • heterocyclic groups can be attached at a variety of positions.
  • Typical heterocycles include, for example, imidazolyl, pyridyl, piperazinyl, piperidinyl, azetidinyl, thiazolyl, furyl, triazolyl, benzimidazolyl, benzothiazolyl, benzimidin Azolyl, quinolyl, isoquinolyl, thiazolinyl, quinazolinyl, pyridazinyl, fluorenyl, naphthyridinyl, oxazolyl and quinazolyl.
  • aryl refers to optionally substituted monocyclic and polycyclic aromatic groups having from 3 to 14 backbone carbon or heteroatoms, and includes carbocyclic aryl and heterocyclic aryl.
  • a carbocyclic aryl group is an aryl group in which all of the ring atoms in the aromatic ring are carbon.
  • heteroaryl refers herein to an aryl group having from 1 to 4 heteroatoms in the aromatic ring as a ring atom and the remaining ring atoms being carbon atoms.
  • polycyclic aryl refers herein to a fused and non-fused cyclic structure in which at least one ring structure is aromatic, such as a benzodioxolane ring. (It has a heterocyclic structure fused to a phenyl group, that is, a naphthyl group or the like).
  • Examples of the aryl moiety used as a substituent in the compound of the present invention include phenyl, pyridyl, pyrrolyl, thiazolyl, indolyl, imidazolyl, oxadiazolyl, tetrazolyl, pyrazinyl, triazole A group, a thienyl group, a furyl group, a quinolyl group, a fluorenyl group, a naphthyl group, a benzothiazolyl group, a benzopyridyl group, a benzimidazolyl group, and the like.
  • substituent groups include, for example, hydroxy, nitro, amino, imino, cyano , halogen, thio group, sulfonyl group, thioamido, sulfhydryl, fluorenylene, oxamidino, methoxamidino, sulfhydryl, sulfonylamino, Carboxyl, formyl, lower alkyl, halogenated lower alkyl, lower alkylamino, halogenated lower alkylamino, lower alkoxy, halogenated lower alkoxy, lower alkoxyalkyl, alkylcarbonyl, Aminocarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl, alkylthio, amino
  • Substituted substituents can be linear, branched or cyclic arrangements of covalently bonded carbon or heteroatoms.
  • the above definition does not include impermissible substitution patterns (for example, a methyl group substituted by five fluorine groups or a halogen atom substituted by another halogen atom); such a mode of substitution which is not allowed is well known to those skilled in the art. .
  • the compounds of the invention or their tautomers, and pharmaceutically acceptable salts, esters, metabolites and prodrugs thereof, may comprise asymmetrically substituted carbon atoms.
  • Such asymmetrically substituted carbon atoms can give rise to the compounds of the invention in enantiomers, diastereomers and other stereoisomeric forms which can be defined in terms of absolute stereochemistry, such as (R)- Or (S)-form.
  • absolute stereochemistry such as (R)- Or (S)-form.
  • all such possible isomers of the compounds of the invention, their individual stereoisomers in optically pure form, mixtures thereof, racemic mixtures (or “racemates"), diastereomers Mixtures as well as individual diastereomers are included in the present invention.
  • pharmaceutically acceptable salt refers to a non-toxic acid or alkaline earth metal salt of a compound of formula I. These salts can be prepared in situ during the final isolation and purification of the compound of formula I, or can be prepared by separately reacting a base or acid functional group with a suitable organic or inorganic acid or base.
  • Typical salts include, but are not limited to, the following salts: acetate, adipate, alginate, citric acid Salt, aspartate, benzoate, besylate, hydrogen sulfate, butyrate, camphorate, sulfonate, digluconate, cyclopentane propionate, dodecyl Sulfate, ethanesulfonate, glucoheptonate, glycerol phosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyl Ethyl sulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, alanate, persulfate, 3-benzene Propionate, picrate, pivalate, propionate, succinate,
  • Reagents such as lower alkyl halides such as methyl, ethyl, propyl and butyl chloride, bromide and iodide; dialkyl sulfates such as dimethyl sulfate, diethyl ester, dibutyl ester may also be used.
  • diamyl esters, long chain halides such as decyl, lauryl, myristyl and stearyl chloride, bromide and iodide, aralkyl halides such as benzyl bromide and phenethyl bromide will contain The basic nitrogen group is quaternized. Water or oil soluble or water or oil dispersible products are thus obtained.
  • Examples of the acid which can be used to form a pharmaceutically acceptable acid addition salt include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, and organic acids such as oxalic acid, maleic acid, methanesulfonic acid, succinic acid and citric acid.
  • the base addition salt can be prepared in situ during the final isolation and purification of the compound of formula (I), or can be obtained by reacting a carboxylic acid moiety with a suitable base such as a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation. It can be prepared by reacting ammonia or an organic primary, secondary or tertiary amine.
  • Pharmaceutically acceptable salts include, but are not limited to, alkali and alkaline earth metal based cations such as sodium, lithium, potassium, calcium, magnesium, aluminum salts, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium.
  • Other typical organic limbs used to form base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.
  • esters which hydrolyze in vivo, including those which are readily decomposed in the human body to release the parent compound or a salt thereof.
  • Suitable esters include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic acids, alkenoic acids, naphthenic acids and alkanoic acids, wherein each alkyl or alkenyl moiety preferably has No more than 6 carbon atoms.
  • Examples of specific esters include formates, acetates, propionates, butyrates, acrylates, and ethylsuccinates.
  • prodrug means that it is suitable for contact with tissues of humans and lower animals in a reasonable medical judgment without excessive toxicity, irritation, allergic reaction, etc., with reasonable benefits/risks.
  • prodrug refers to a compound that is rapidly converted in vivo, for example by hydrolysis in blood, to produce the parent compound of the above formula.
  • T. Higuchi and v. Stella as a Pro-drugs as Novel Delivery Systems, Vol.14, ACSSymposium Series and Edward B. Roche, Bioreversible Vectors in Drug Design ( A detailed discussion is provided in Bioreversible Carriers in Drug Design, both of which are incorporated herein by reference.
  • any structural formula given herein also represents an unlabeled form as well as an isotopically labeled form of the compound.
  • Isotopically labeled compounds have the structure described by the structural formula shown herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes which may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, ll C, 13 C, 14 C, 15 N, 18 F , 31 P, 32 P, 35 S, 36 Cl, 125 I.
  • the invention includes various isotopically-labeled compounds of the present invention, such as those in which radioactive isotopes such as 3 H and 14 C are present.
  • isotopically labeled compounds can be used in metabolic studies (using 14 C), reaction kinetic studies (using, for example, 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computers.
  • PET positron emission tomography
  • PET positron emission tomography
  • SPECT single photon emission computers
  • 18 F or labeled compounds are particularly useful for PET or SPECT studies.
  • Isotopically labeled compounds of the invention can generally be prepared by the practice procedures or procedures disclosed in the Examples and Preparations below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • replacement with heavier isotopes particularly deuterium (ie, 2 H or D)
  • ruthenium in this context is considered to be a substituent of the compound of formula (1).
  • the concentration of such heavier isotopes, especially strontium can be defined by isotopic enrichment factors.
  • isotopic enrichment factor refers to the ratio between the isotope abundance and the natural abundance of a given isotope. If a substituent in the compound of the present invention is designated as hydrazine, the compound has at least 3,500 (52.5% of ruthenium mixed in each designated atom) and at least 4,000 (60% of ruthenium mixed) for each of the specified ruthenium atoms.
  • Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or can be replaced by suitable isotopically labeled reagents by methods analogous to those described in the accompanying examples and preparations. The non-isotopically labeled reagents used were prepared.
  • the compounds of the present invention can be passed It is metabolized in the human or animal body or cells and processed in the body to produce metabolites.
  • the term "metabolite” as used herein refers to any structural derivative produced in an individual after administration of the parent compound. These derivatives can be produced from the parent compound by various biochemical transformations such as oxidation, reduction, hydrolysis or binding in the body, and include, for example, oxides and demethylated derivatives. Metabolites of the compounds of the invention can be identified using conventional techniques known in the art. See, for example, Bertolini, G. et al.,]. Med.
  • cancer refers to a cancerous disease which can be beneficially treated by inhibiting PIM kinase, including, for example, including, for example, solid tumors such as lung cancer, pancreatic cancer, thyroid cancer, ovarian cancer, bladder cancer, breast cancer, prostate cancer or colon.
  • solid tumors such as lung cancer, pancreatic cancer, thyroid cancer, ovarian cancer, bladder cancer, breast cancer, prostate cancer or colon.
  • melanoma bone marrow disorders such as myeloid leukemia, multiple myeloma and erythroleukemia, adenomas, for example, villous colon adenomas and sarcomas such as osteosarcoma; liquid tumors such as chronic lymphocytic leukemia, acute lymphocytes Leukemia, acute myeloid leukemia, chronic myeloid leukemia, non-Hodgkin's lymphoma, and multiple myeloma.
  • the PIM kinase inhibitors provided by the present invention include the following compounds:
  • Another object of the present invention is to provide a process for the preparation of the above PIM kinase inhibitor.
  • the compounds of the invention are prepared starting from commercially available starting materials and reagents.
  • the method of the present invention is represented by the following formula:
  • the alcohol B (1.1 equivalents) with or without a protecting group is first reacted with a base such as NaH (1.1 equivalents) in a solvent such as tetrahydrofuran at room temperature (25 ° C) for 1 hour, then Further, an aminopyrimidine ether C is obtained by reacting with 5-amino-4-chloropyrimidine A (1 equivalent) under heating at, for example, 100 ° C for 1 to 10 hours.
  • Aromatic carboxylic acid D (1 equivalent) with or without a protecting group in the presence of a coupling reagent such as HATU (1.1 equivalents), a base such as DIEA (3 equivalents) in a solvent such as DMF and amine C ( 1 equivalent) was reacted to give an ether compound E.
  • E is an ether compound of the formula I in which the E substituent is a hydrocarbyloxy group.
  • a protecting group such as BOC (tert-butoxyformate) or trimethylsilane
  • E with 10 to 100 equivalents of trifluoroacetic acid and an equal volume of dichloromethane, or 2 equivalents of hydrochloric acid
  • the mixture was stirred for 1 to 16 hours, and then the solvent was distilled off under reduced pressure at room temperature (25 ° C) to give an ether compound of the formula I in which the E substituent was a hydrocarbyloxy group.
  • a further object of the present invention is to provide the use of the above PIM kinase inhibitors in pharmaceuticals.
  • the PIM kinase inhibitor of the present invention can be used for the preparation of a medicament.
  • the present invention provides the use of the above PIM kinase inhibitor for the preparation of a medicament for treating or preventing an autoimmune disease.
  • the present invention provides the use of the above PIM kinase inhibitor for the preparation of a medicament for treating or preventing an allergic disease.
  • the present invention provides the use of the above PIM kinase inhibitor for the preparation of a medicament for treating or preventing atherosclerosis.
  • the present invention provides the use of the above PIM kinase inhibitor for the preparation of a medicament for treating or preventing an anti-organ transplant rejection.
  • the invention provides the use of the above PIM kinase inhibitor for the preparation of a medicament for treating or preventing cancer.
  • the present invention provides the use of the above PIM kinase inhibitor for the preparation of a medicament for treating or preventing multi-directional drug resistance.
  • the present invention provides the use of the above PIM kinase inhibitor for the preparation of a medicament for treating or preventing T cell mediated inflammation.
  • the medicament of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a PIM kinase inhibitor as an active ingredient and a pharmaceutically acceptable carrier.
  • the present invention provides a novel use of a PIM kinase inhibitor, which has great clinical application value.
  • the compounds and pharmaceutical compositions of the present invention are useful for treating or preventing cancer, reversing anticancer and other drug resistance, inflammatory bowel disease, autoimmune diseases, allergic diseases, arterial porridge Sclerosis, anti-organ transplant rejection, multi-directional drug resistance, T cell-mediated inflammation;
  • cancer refers to cancerous diseases that can be beneficially treated by inhibiting PIM kinase, including, for example, solid tumors such as lung cancer, pancreas Cancer, thyroid cancer, ovarian cancer, bladder cancer, breast cancer, prostate cancer or colon cancer, melanoma, bone marrow disorders such as myeloid leukemia, multiple myeloma and erythroleukemia, gland Tumors such as, villous colon adenomas and sarcomas such as osteosarcoma; liquid tumors such as chronic lymphocytic leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, non-Hodg
  • the present invention provides the compound and the pharmaceutical composition described above for the preparation of a medicament for treating or preventing cancer, reversing anti-cancer and other drug resistance, inflammatory bowel disease, autoimmune disease, allergic reaction disease, Atherosclerosis, anti-organ transplant rejection, multi-directional resistance, T cell-mediated inflammation;
  • cancer refers to cancerous diseases that can be beneficially treated by inhibiting PIM kinase, including, for example, solid tumors such as lung cancer , pancreatic cancer, thyroid cancer, ovarian cancer, bladder cancer, breast cancer, prostate cancer or colon cancer, melanoma, bone marrow disorders such as myeloid leukemia, multiple myeloma and erythroleukemia, adenomas, for example, villous colon glands Tumors and sarcomas such as osteosarcoma; liquid tumors such as chronic lymphocytic leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic myeloid
  • the product (h) is obtained by using methyl 3-amino-6-bromo-5-fluoro-2-picolinate (g) as a raw material.
  • Example 1 The preparation method is referred to in Example 1. Wherein the compound B1 of the step (1) is replaced with 3-hydroxymethyl-azetidin-1-carboxylic acid tert-butyl ester (B2) to give the product 2.
  • B2 3-hydroxymethyl-azetidin-1-carboxylic acid tert-butyl ester
  • Example 1 The preparation method is referred to in Example 1. Wherein the compound B1 of the step (1) is replaced with 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (B3) to give the product 3.
  • B3 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester
  • Example 1 The preparation method is referred to in Example 1. Wherein the compound B1 of the step (1) is replaced with 3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (B4) to give the product 4.
  • B4 3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester
  • Example 1 The preparation method is referred to in Example 1. Wherein the compound B1 of the step (1) is replaced with 3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (B5) to give the product 5.
  • Example 1 The preparation method is referred to in Example 1. Wherein the compound B1 of the step (1) is replaced with 4-hydroxy-azetidin-1-carboxylic acid tert-butyl ester (B6) to give the product 6.
  • Example 1 The preparation method is referred to in Example 1. Wherein the compound B1 of the step (1) is replaced with 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (B7) to give the product 7.
  • Example 1 The preparation method is referred to in Example 1. Wherein the compound B1 of the step (1) is replaced with 3-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (B8) to give the product 8.
  • Example 1 The preparation method is referred to in Example 1. Wherein the compound B1 of the step (1) is replaced with tert-butyl 3-hydroxy-1-azetidincarboxylate (B9) to give the product 9.
  • Example 1 The preparation method is referred to in Example 1. Wherein compound B1 of step (1) is replaced with trans-4-hydroxy-cyclohexyl-carbamic acid tert-butyl ester (B10) to give product 10.
  • Example 1 The preparation method is referred to in Example 1. Wherein the compound B1 of the step (1) is replaced with 3-hydroxy-cyclohexyl-carbamic acid tert-butyl ester (B11) to give the product 11.
  • Example 1 The preparation method is referred to in Example 1. Wherein compound B1 of step (1) is replaced with 3-hydroxypropylamine-1-carboxylic acid tert-butyl ester (B12) to give product 12.
  • Example 1 The preparation method is referred to in Example 1. Wherein the compound B1 of the step (1) is replaced with N-methyl-3-hydroxypropylamine-1-carboxylic acid tert-butyl ester (B13) to give the product 13.
  • Example 1 The preparation method is referred to in Example 1. Wherein the compound B1 of the step (1) is replaced with N,N-dimethyl-3-hydroxypropylamine (B14), and the deprotection of the step (3) is omitted to obtain the product 14.
  • B14 N,N-dimethyl-3-hydroxypropylamine
  • Example 1 The preparation method is referred to in Example 1. Wherein the compound B1 of the step (1) is replaced with 4-hydroxybutylamine-1-carboxylic acid tert-butyl ester (B15) to give the product 15.
  • Example 1 The preparation method is referred to in Example 1. Wherein compound B1 of step (1) is replaced with N-methyl-4-hydroxybutylamine-1-carboxylic acid tert-butyl ester (B16) to give product 16.
  • Example 1 The preparation method is referred to in Example 1. Wherein the compound B1 of the step (1) is replaced with 1,3-propanediol (B17), and the deprotection of the step (3) is omitted to obtain the product 17.
  • Example 1 The preparation method is referred to in Example 1. Wherein the compound B1 of the step (1) is replaced with 1,3-butanediol (B18), and the deprotection of the step (3) is omitted to obtain the product 18.
  • B18 1,3-butanediol
  • Example 1 The preparation method is referred to in Example 1. Wherein the compound B1 of the step (1) is replaced with 1,4-butanediol (B19), and the deprotection of the step (3) is omitted to obtain the product 19.
  • Example 1 The preparation method is referred to in Example 1. Wherein the compound B1 of the step (1) is replaced with 4-methyl-1,4-pentanediol (B20), and the deprotection of the step (3) is omitted to obtain the product 20.
  • B20 4-methyl-1,4-pentanediol
  • the preparation method is as follows. The method of the steps (1) and (2) in the embodiment 1, wherein the compound B1 of the step (1) is (2,2-dimethyl-1,3-dioxocyclopentan-4-yl) Substituting ethanol (B21) to produce product E21.
  • Example 1 The preparation method is referred to in Example 1. Wherein the compound B1 of the step (1) is replaced with tetrahydropyran-4-methanol (B22), and the deprotection of the step (3) is omitted to obtain the product 22.
  • B22 tetrahydropyran-4-methanol
  • Example 1 The preparation method is referred to in Example 1. Wherein the compound D1 of the step (2) is replaced with 3-amino-6-(2,6-difluoro-phenyl)-5-fluoro-2-pyridinecarboxylic acid (D2) to give the product 23.
  • Example 23 The preparation method is referred to Example 23. Wherein compound B1 of step (1) is replaced with B4 to give product 24.
  • Example 23 The preparation method is referred to Example 23. Wherein the compound B1 of the step (1) is replaced with B3 to obtain the product 25.
  • Example 23 The preparation method is referred to Example 23. Wherein compound B1 of step (1) is replaced with B6 to give product 26.
  • Example 23 The preparation method is referred to Example 23. Wherein compound B1 of step (1) is replaced with B10 to give product 27.
  • Example 23 The preparation method is referred to Example 23. Wherein compound B1 of step (1) is replaced with B8 to give product 28.
  • Example 29 The preparation method is referred to Example 29. Compound 9 was replaced with 2 to give product 30.
  • Example 23 The preparation method is referred to Example 23. Wherein the compound B1 of the step (1) is replaced with B9 to obtain the product 31.
  • Example 23 The preparation method is referred to Example 23. Wherein compound B1 of step (1) is replaced with B2 to give product 32.
  • Example 29 The preparation method is referred to Example 29. Compound 9 was replaced with compound 31 to give product 33.
  • Example 29 The preparation method is referred to Example 29. Compound 9 was replaced with compound 32 to give product 34.
  • Example 1 The preparation method is referred to in Example 1. Wherein the compound B1 of the step (1) is replaced with B4, and the compound D1 of the step (2) is replaced with 3-amino-5-fluoro-6-phenyl)-2-pyridinecarboxylic acid (D3) to give the product 35.
  • Example 1 The preparation method is referred to in Example 1. Wherein the compound B1 of the step (1) is replaced with B3, and the compound D1 of the step (2) is replaced with 3-fluoro-(2,4'-pyridine)-6-carboxylic acid (D4) to obtain the product 36.
  • Example 1 The preparation method is referred to in Example 1. Wherein the compound B1 of the step (1) is replaced with B6, and the compound D1 of the step (2) is replaced with 6-(2,6-difluoro-phenyl)-3-fluoropyridinecarboxylic acid (D5) to obtain the product 37.
  • Example 1 The preparation method is referred to in Example 1. Wherein the compound B1 of the step (1) is replaced with 4-hydroxy-azetidin-1-carboxylic acid tert-butyl ester (B6), and the compound D1 of the step (2) is 6-(2,6-difluorophenyl). Substituting -5-trifluoromethyl-2-picolinic acid (D6) gave product 39.
  • Example 1 The preparation method is referred to in Example 1. Wherein the compound D1 of the step (2) is replaced with 6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridinecarboxylic acid (D6) to give the product 40.
  • D6 6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridinecarboxylic acid
  • Example 1 The preparation method is referred to in Example 1. Wherein the compound B1 of the step (1) is replaced with 3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester (B2), and the compound D1 of the step (2) is used for 6-(2,6-difluorobenzene). Substituting -5-trifluoromethyl-2-picolinic acid (D6) to give the product 41.
  • Example 1 The preparation method is referred to in Example 1. Wherein compound B1 of step (1) is replaced with 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (B3), and compound D1 of step (2) is treated with 6-(2,6-difluorophenyl)-5- Instead of trifluoromethyl-2-picolinic acid (D6), product 42 was obtained.
  • Example 1 The preparation method is referred to in Example 1. Wherein compound B1 of step (1) is replaced with t-butyl-cyclohexyl-carbamic acid tert-butyl ester (B10), and compound D1 of step (2) is treated with 6-(2,6-difluorophenyl)-5. Substituting trifluoromethyl-2-picolinic acid (D6) to give the product 43.
  • Example 1 The preparation method is referred to in Example 1. Wherein compound B1 of step (1) is replaced by tetrahydropyran-4-methanol (B22), and compound D1 of step (2) is treated with 6-(2,6-difluorophenyl)-5-trifluoromethyl- Substituting 2-picolinic acid (D6), the deprotection of step (3) is omitted, and product 44 is obtained.
  • Example 1 The preparation method is referred to in Example 1. Wherein the compound B1 of the step (1) is replaced with 4-hydroxy-azetidin-1-carboxylic acid tert-butyl ester (B6), and the compound D1 of the step (2) is 3-amino-6-(2,6- Substituting difluorophenyl)-5-trifluoromethyl-2-pyridinecarboxylic acid (D7) to give the product 45.
  • B6 4-hydroxy-azetidin-1-carboxylic acid tert-butyl ester
  • D7 3-amino-6-(2,6- Substituting difluorophenyl)-5-trifluoromethyl-2-pyridinecarboxylic acid
  • Example 1 The preparation method is referred to in Example 1. Wherein the compound D1 of the step (2) is replaced with 3-amino-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridinecarboxylic acid (D7) to give the product 46.
  • Example 1 The preparation method is referred to in Example 1. Wherein the compound B1 of the step (1) is replaced with 3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester (B2), and the compound D1 of the step (2) is 3-amino-6-(2, Substituting 6-difluorophenyl)-5-trifluoromethyl-2-pyridinecarboxylic acid (D7) gave product 47.
  • Example 1 The preparation method is referred to in Example 1. Wherein the compound B1 of the step (1) is replaced with 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (B3), and the compound D1 of the step (2) is 3-amino-6-(2,6-difluorobenzene). Substituting -5-trifluoromethyl-2-picolinic acid (D7) afforded product 48.
  • Example 1 The preparation method is referred to in Example 1. Wherein the compound B1 of the step (1) is replaced with trans-4-hydroxy-cyclohexyl-carbamic acid tert-butyl ester (B10), and the compound D1 of the step (2) is 3-amino-6-(2,6-difluoro Substituting phenyl)-5-trifluoromethyl-2-picolinic acid (D7) gave product 49.
  • Example 1 The preparation method is referred to in Example 1. Wherein the compound B1 of the step (1) is replaced with 3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (B4), and the compound D1 of the step (2) is 3-amino-6-(2,6-difluorobenzene). Substituting 5-aminotrifluoromethyl-2-pyridinecarboxylic acid (D7) to give the product 50.
  • Example 29 The preparation method is referred to Example 29. Compound 9 was replaced with compound 41 to give product 51.
  • Example 29 The preparation method is referred to Example 29. Compound 9 was replaced with compound 47 to give product 52.
  • Example 53 The preparation method is referred to Example 53.
  • Compound 2 was replaced with compound 32 to give product 54.
  • Example 53 The preparation method is referred to Example 53.
  • Compound 2 was replaced with compound 41 to give product 55.
  • Example 53 The preparation method is referred to Example 53.
  • Compound 2 was replaced with compound 47 to give product 56.
  • the biological activities of the compounds of the present invention were entrusted to Baonuo Technology (Beijing) Co., Ltd. (E, No. 29, Life Science Park Road, Changping District, Beijing) for testing.
  • the test method is the in vitro activity assay of kinase PIM - IMAP fluorescence polarization method
  • PIM is a serine/threonine protein kinase that phosphorylates 5-FAM-labeled small peptide substrates.
  • the unphosphorylated substrate could not bind to the binding reagent (immobilized metal chelate beads) and the fluorescence polarization value was low.
  • the phosphorylated small peptide can be bound to the binding reagent such that the fluorescence polarization value is increased.
  • the degree of phosphorylation of 5-FAM-labeled small peptide substrates reflects the magnitude of PIM kinase activity.
  • the ability of these compounds to inhibit PIM kinase activity can be determined by testing the inhibitory effect of the compounds of the invention on PIM kinase activity at a concentration.
  • PIM1 (Millipore Cat. No. 14-573) (purchased from Millipore Corporation, USA)
  • 5-FAM-labeled small peptide (5-FAM-RSRHSSYPAGT, AnaSpec catalog #63801) (purchased from AnaSpec Inc., USA)
  • IMAP Progressive binding reagent IMAP binder
  • Tris-HCl trishydroxymethylaminomethane-hydrochloric acid
  • Triton X-100 polyethylene glycol octylphenyl ether X-100: 0.01%
  • IMAP binding agent containing 75% IMAP Binding Buffer A, 25% IMAP Binding Buffer B, 1/600 immobilized metal chelate beads
  • the reading plate has a fluorescence polarization value mP, excitation light of 485 nm, and emission light of 530 nm.
  • Percent inhibition (fluorescence polarization value mP - minimum value ⁇ 100 / (maximum - minimum value)
  • PIM kinase activity by biochemical assays to test all compounds in the examples are embodiments of PIM-1, PIM-2 and PIM-3 kinase activity significantly inhibited, an IC 50 in the range of 0.1-500nM.

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Abstract

La présente invention concerne un inhibiteur de la PIM kinase, un procédé de préparation associé et son application. Une formule structurelle de celui-ci est un composé tel que représenté par la formule générale I suivante. L'invention concerne également un stéréoisomère, un tautomère et un sel pharmaceutique du composé dans la formule générale I. Le composé de formule générale I possède une fonction inhibitrice évidente sur l'activité de la kinase, peut être utilisé comme inhibiteur de la PIM kinase, peut être utilisé pour préparer un médicament destiné à traiter ou à prévenir un cancer, pour inverser la chimiorésistance ou la résistance à d'autres médicaments, pour traiter ou prévenir des maladies intestinales inflammatoires chroniques, des maladies auto-immunes et analogues, et présente une grande valeur d'application clinique.
PCT/CN2016/099040 2015-09-18 2016-09-14 Dérivé de pyrimidine inhibiteur de la pim kinase, son procédé de préparation et son application dans la préparation de médicaments WO2017045612A1 (fr)

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